The enzyme at the center of the story is lactate dehydrogenase A, or LDHA, the workhorse protein that converts pyruvate into lactate at the end of the glycolytic pathway. In many tumors, LDHA activity allows cells to keep producing energy even when oxygen is scarce, a metabolic mode reminiscent of fermentation. It also generates lactate, a molecule that tumors exploit as a signaling agent and as a building block for chemical modifications on histone proteins. Yet for all its importance, the mechanisms that keep LDHA protein stable inside colorectal cancer cells have remained poorly charted. The new study set out to fill that gap by asking a deceptively simple question: what protects LDHA from being destroyed?

To answer it, the researchers turned to affinity purification followed by mass spectrometry, a technique that fishes out the proteins that physically associate with a molecule of interest. Among the partners they captured was TRIP13, an AAA+ ATPase, a member of a family of ring-shaped motor proteins that use the energy of ATP hydrolysis to remodel other proteins. TRIP13 is already known to cancer biologists for its role in spindle assembly checkpoint signaling and in the repair of meiotic recombination intermediates, and elevated TRIP13 levels have been linked to poor outcomes in several tumor types. The mass spectrometry data suggested something unexpected: TRIP13 was not just a casual acquaintance of LDHA but a genuine binding partner, a result the team confirmed using co-immunoprecipitation experiments.

The functional consequences of that partnership proved striking. When the researchers depleted TRIP13 from colorectal cancer cells, LDHA protein abundance collapsed and the remaining LDHA became far less stable, while the amount of ubiquitin attached to LDHA rose sharply. Notably, the levels of LDHA messenger RNA barely changed, indicating that TRIP13 was acting after the gene had been read, at the level of protein degradation rather than protein production. In other words, TRIP13 was not telling the cell to make more LDHA; it was preventing the cell from throwing LDHA away.

The destruction pathway that TRIP13 blocks turned out to be mediated by FBXW7, a well-characterized substrate-recognition component of the SCF ubiquitin ligase complex. FBXW7 acts as a quality-control scout, binding specific sequence motifs on target proteins and tagging them for delivery to the proteasome, the cellular garbage disposal. FBXW7 is famous as a tumor suppressor, and its loss is common in many cancers, but the new work reveals a metabolic dimension to its activity: it can tag LDHA for degradation. TRIP13, the researchers found, competes with FBXW7 for access to LDHA. By occupying the enzyme, TRIP13 limits FBXW7 association, suppressing FBXW7-dependent ubiquitination and the subsequent proteasomal destruction of LDHA. Experiments with purified proteins provided direct evidence for this competition, showing that the two molecules vie for the same binding surface on LDHA rather than acting through intermediaries.

The binding interface itself carries mechanistic weight. TRIP13 attaches to LDHA through its AAA+ ATPase-associated region, and the team engineered a mutant lacking this domain, TRIP13-ΔAAA+, to test whether the physical connection was essential. It was. Wild-type TRIP13 could stabilize LDHA and sustain the metabolic program, while the binding-defective mutant could not. This mutant-based approach transformed the study from correlation into causation: the protective effect on LDHA required the physical handshake between the two proteins, not some indirect influence of TRIP13 on cell state.

What does stabilized LDHA actually buy a tumor cell? Quite a lot, it turns out, especially under hypoxia. When TRIP13 was present, colorectal cancer cells maintained glycolytic activity and lactate production even when oxygen was scarce, a capacity the authors describe as glycolytic plasticity, the ability to keep the fermentative metabolic mode running under stress. When TRIP13 was removed, LDHA levels fell, glycolysis weakened, and the cells became flooded with oxidative stress, the damaging accumulation of reactive oxygen species that hypoxic cells normally manage with elaborate antioxidant defenses. The loss of TRIP13 also made the cells dramatically more sensitive to oxaliplatin, one of the standard chemotherapy drugs for colorectal cancer, which works in part by generating oxidative damage.

The rescue experiments revealed the logic of the pathway with unusual clarity. Restoring LDHA, supplementing the cells with lactate, or depleting FBXW7 all partially rescued the vulnerabilities created by TRIP13 loss, confirming that the TRIP13–LDHA–FBXW7 axis is the operative circuit. The lactate connection opened an even more intriguing chapter. Elevated lactate, the team found, fuels a p300-dependent program of histone lactylation, a chemical modification in which lactate-derived groups attach to histone proteins and alter gene expression. Specifically, lactylation of histone H3 at lysine 18, abbreviated H3K18la, promoted the expression of antioxidant genes including GCLC, which encodes a subunit of the glutathione synthesis machinery, and SLC7A11, a component of the cystine transport system that supports glutathione production. In essence, the lactate produced by stabilized LDHA does not merely sit in the cell as metabolic waste; it becomes a signal that reprograms gene expression to build the cell’s antioxidant armor.

The pharmacological and genetic tests of p300 reinforced this epigenetic arm of the pathway. When p300 activity was blocked, either with drugs or by genetic means, the lactate-driven antioxidant program weakened, confirming that the histone-modifying enzyme p300 is the conduit through which lactate translates into defensive gene expression. The team then took the story into living animals, using xenograft models in which human colorectal cancer cells are implanted in mice. Consistent with the cell-based findings, tumors expressing wild-type TRIP13 grew robustly, while those carrying the LDHA-binding-defective TRIP13-ΔAAA+ mutant failed to sustain the metabolic program, demonstrating that the physical TRIP13–LDHA interaction underpins tumor growth in vivo.

The therapeutic implications are considerable. Colorectal cancer remains one of the most common malignancies worldwide, and resistance to oxaliplatin-based chemotherapy is a major barrier to curative treatment. The new study suggests that TRIP13-dependent LDHA stabilization is a central mechanism by which tumor cells maintain redox homeostasis, the balance between oxidative damage and antioxidant defense, under hypoxic stress, and that this same mechanism underlies chemoresistance. Targeting the TRIP13–LDHA interaction, or the downstream lactate–p300–H3K18la antioxidant program, could therefore strip tumor cells of the metabolic flexibility they need to survive treatment. The work also adds a metabolic twist to the biology of FBXW7, a tumor suppressor whose substrate-recognition activity now includes a key glycolytic enzyme. As with any preclinical study, the path from xenograft models to patients will require further validation, and the tools to disrupt the TRIP13–LDHA handshake in humans are still under development. But the study provides a detailed molecular map of how colorectal cancer cells guard their metabolic machinery, and it identifies a specific, druggable-looking circuit whose disruption could resensitize chemoresistant tumors to standard therapy.

Subject of Research: TRIP13-mediated stabilization of LDHA against FBXW7-dependent ubiquitination and its role in glycolytic plasticity and oxaliplatin resistance in colorectal cancer

Article Title: TRIP13 protects LDHA from FBXW7-mediated degradation and drives glycolytic plasticity in colorectal cancer

Article References: Sheng, N., He, Q., Wang, J., Zhou, S., Gu, Y., Gong, J., He, P., Chen, H., & Wang, Z. (2026). TRIP13 protects LDHA from FBXW7-mediated degradation and drives glycolytic plasticity in colorectal cancer. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03858-5

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03858-5

Keywords: TRIP13, LDHA, FBXW7, ubiquitination, glycolysis, lactate, H3K18 lactylation, oxaliplatin resistance, colorectal cancer, cancer metabolism, hypoxia, proteostasis